New Quantitative Neuroimaging Metrics of Structural and Functional Connectivity of the Locus Coeruleus as a Novel Biomarker of Alzheimer's Disease Pathogenesis and Progression

蓝斑结构和功能连接性的新定量神经影像指标作为阿尔茨海默病发病机制和进展的新型生物标志物

基本信息

批准号：
10326564
负责人：
Mark W Bondi
金额：
$ 35.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-04-30
项目状态：
已结题

项目摘要

The original theory offered by Braak & Braak (1991)—that neurofibrillary tangle pathology proceeds along well- defined predilection sites beginning in the medial temporal cortex—has been modified by the same author to suggest that the pathologic process instead commences in the lower brainstem (Braak et al. 2011). The first visible pathologic changes are now thought to occur in the locus coeruleus (LC) and then spread via its axonal projections to transentorhinal/entorhinal cortex (TEC). We propose to study LC change using a novel computational morphology method, combined with novel methods of measuring white matter microstructural tractography and functional connectivity to TEC. These new methods are designed to overcome major limitations in current neuro-MRI analysis methods that limit the ability to detect subtle structural and functional changes associated with early AD. Such alterations across the aging-MCI-AD continuum, as well as in those cognitively normal individuals with risk factors for AD (e.g., CSF AD biomarkers; apolipoprotein E ε4 carriers), would provide significant advances in our understanding of the pathogenesis of AD across clinical transition points and perhaps during this `silent' period (i.e., prior to the occurrence of traditional AD biomarker positivities). Using our newly developed diagnostic and MRI metrics, we propose to quantify variations in LC morphology and its projections to TEC (termed the LC-TEC system). Aim 1. Examine locus coeruleus morphology, contrast, and associated cortical thickness. In this supplement, we propose to augment the structural morphology estimates with our newly developed Joint Estimation Diffusion (JEDI) method (Frank et al., 2020) to provide improved sensitivity to the assessment of gray matter (GM) tissue characteristics. We hypothesize that this greater sensitivity will produce greater distinctions in LC morphology, contrast and associated cortical thickness—particularly in vulnerable TEC and hippocampal regions—along the aging-MCI-AD continuum. Aim 2. Examine structural connectivity of the LC-TEC system. In this supplement, we propose to augment the diffusion analysis with our newly developed JEDI method that provides sensitivity to sub-voxel (microscopic) diffusion anisotropy, facilitating assessment of GM tissue status, and improving anisotropy estimates in white matter (WM). We hypothesize that this greater sensitivity will produce more accurate estimates of structural connectivity derived from the local anisotropy measures in the LC-TEC system. Aim 3. Examine functional connectivity of the LC-TEC system.In this supplement, we propose to supplement the functional modes and connectivity estimates with functional tractography augmented by averaged structural GM/WM tissue constraints derived from our JEDI method to provide improved sensitivity to the assessment of functional modes and connectivity. We hypothesize that this greater sensitivity will produce better clustering of abnormal functional modes and greater distinctions in connectivity patterns for the aging-MCI-AD continuum.

Braak＆Braak（1991）提供的原始理论 - 神经纤维缠结的病理学沿着良好定义的预测站点从内侧临时皮层开始 - 同一作者修改了暗示病理过程是从脑干下部开始的（Braak等，2011）。第一个现在认为可见的病理变化发生在基因座（LC）中，然后通过其轴突传播投影到跨肾/内嗅皮层（TEC）。我们建议使用小说研究LC变化计算形态方法，结合了测量白质微结构的新方法拖拉术和与TEC的功能连通性。这些新方法旨在克服专业当前神经-MRI分析方法的局限性限制了检测细微的结构和功能的能力与早期广告相关的变化。在衰老的MCI-AD连续体中进行的此类改变以及具有AD风险因素的认知正常人（例如CSF AD生物标志物；载脂蛋白Eε4载体），将在我们对跨临床转变的AD发病机理的理解方面带来重大进展要点，也许在这个“沉默”时期（即，在发生传统广告生物标志物之前使用我们新开发的诊断和MRI指标，我们建议量化LC的变化形态及其对TEC的项目（称为LC-TEC系统）。 AIM 1。检查层层的形态，对比度和相关的皮质厚度。在此补充中，我们建议通过新开发的联合估计来增强结构形态的估计扩散（绝地武士）方法（Frank等，2020），以提高对灰质评估的敏感性（GM）组织特征。我们假设这种更大的灵敏度将在LC中产生更大的区别形态，对比度和相关的皮质厚度 - 尤其是在脆弱的TEC和海马中区域 - 以及衰老的MCI-AD连续体。目标2。检查LC-TEC系统的结构连接性。在这种补充中，我们建议通过我们新开发的绝地武士方法来增强扩散分析对亚素（显微镜）扩散各向异性提供敏感性，支持对GM组织状态的评估，并改善白质（WM）的各向异性估计值。我们假设这种更大的敏感性将会从局部各向异性测量中得出的结构连通性产生更准确的估计。 LC-TEC系统。目标3。检查LC-TEC系统的功能连接性。在此补充中，我们通过功能拖拉学补充功能模式和连接性估计的建议通过从我们的绝地武士方法得出的平均结构GM/WM组织约束来增强提高了对功能模式和连通性评估的敏感性。我们假设这更大敏感性将产生更好的功能模式的聚类和连通性的更大区分衰老MCI-AD连续体的模式。